Levetiracetam Reverses Synaptic Deficits Produced by Overexpression of SV2A

Levetiracetam is an FDA-approved drug used to treat epilepsy and other disorders of the nervous system. Although it is known that levetiracetam binds the synaptic vesicle protein SV2A, how drug binding affects synaptic functioning remains unknown. Here we report that levetiracetam reverses the effects of excess SV2A in autaptic hippocampal neurons. Expression of an SV2A-EGFP fusion protein produced a ∼1.5-fold increase in synaptic levels of SV2, and resulted in reduced synaptic release probability. The overexpression phenotype parallels that seen in neurons from SV2 knockout mice, which experience severe seizures. Overexpression of SV2A also increased synaptic levels of the calcium-sensor protein synaptotagmin, an SV2-binding protein whose stability and trafficking are regulated by SV2. Treatment with levetiracetam rescued normal neurotransmission and restored normal levels of SV2 and synaptotagmin at the synapse. These results indicate that changes in SV2 expression in either direction impact neurotransmission, and suggest that levetiracetam may modulate SV2 protein interactions

Management of Patients with Advanced Prostate Cancer. Part I: Intermediate-/High-risk and Locally Advanced Disease, Biochemical Relapse, and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022.

BACKGROUND: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management. OBJECTIVE: To present consensus voting results for select questions from APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. RESULTS AND LIMITATIONS: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis. CONCLUSIONS: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

How populations differentiate despite gene flow: Sexual and natural selection drive phenotypic divergence within a land fish, the Pacific leaping blenny

Background: Divergence between populations in reproductively important features is often vital for speciation. Many studies attempt to identify the cause of population differentiation in phenotype through the study of a specific selection pressure. Holistic studies that consider the interaction of several contrasting forms of selection are more rare. Most studies also fail to consider the history of connectivity among populations and the potential for genetic drift or gene flow to facilitate or limit phenotypic divergence. We examined the interacting effects of natural selection, sexual selection and the history of connectivity on phenotypic differentiation among five populations of the Pacific leaping blenny (Alticus arnoldorum), a land fish endemic to the island of Guam. Results: We found key differences among populations in two male ornaments - the size of a prominent head crest and conspicuousness of a coloured dorsal fin - that reflected a trade-off between the intensity of sexual selection (male biased sex ratios) and natural selection (exposure to predators). This differentiation in ornamentation has occurred despite evidence suggesting extensive gene flow among populations, which implies that the change in ornament expression has been recent (and potentially plastic). Conclusions: Our study provides an early snapshot of divergence in reproductively important features that, regardless of whether it reflects genetic or plastic changes in phenotype, could ultimately form a reproductive barrier among populations. © 2014 Morgans et al.; licensee BioMed Central Ltd

Mechanisms responsible for differential bactericidal activities of human and rabbit complement for<em> Neisseria meningitidis</em>

Years ago, when I was young and reckless, I believed that there was such a thing as an allinclusive domain.1 Now I have come to see the error of my ways. The source of my mistake was a view that might be labeled ‘Tractarianism’. Tractarians believe that language is subject to a metaphysical constraint. In order for an atomic sentence to be true, there needs to be a certain kind of correspondence between the semantic structure of the sentence and the ‘metaphysical structure’ of reality. The purpose of this paper is to explain why I think Tractarianism is mistaken, and what I think an anti-Tractarian should say about absolutely general quantification

Constraining early to middle Eocene climate evolution of the southwest Pacific and Southern Ocean

Studies of early Paleogene climate suffer from the scarcity of well-dated sedimentary records from the southern Pacific Ocean, the largest ocean basin during this time. We present a new magnetostratigraphic record from marine sediments that outcrop along the mid-Waipara River, South Island, New Zealand. Fully oriented samples for paleomagnetic analyses were collected along 45 m of stratigraphic section, which encompasses magnetic polarity Chrons from C23n to C21n (~51.5-47 Ma). These results are integrated with foraminiferal, calcareous nannofossil, and dinoflagellate cyst (dinocyst) biostratigraphy from samples collected in three different expeditions along a total of ~80 m of section. Biostratigraphic data indicates relatively continuous sedimentation from the lower Waipawan to the upper Heretaungan New Zealand stages (i.e., lower Ypresian to lower Lutetian, 55.5 to 46 Ma). We provide the first magnetostratigraphically-calibrated age of 48.88 Ma for the base of the Heretaungan New Zealand stage (latest early Eocene). To improve the correlation of the climate record in this section with other Southern Ocean records, we reviewed the magnetostratigraphy of Ocean Drilling Program (ODP) Site 1172 (East Tasman Plateau) and Integrated Ocean Drilling Program (IODP) Site U1356 (Wilkes Land Margin, Antarctica). A paleomagnetic study of discrete samples could not confirm any reliable magnetic polarity reversals in the early Eocene at Site 1172. We use the robust magneto-biochronology of a succession of dinocyst bioevents that are common to mid-Waipara, Site 1172, and Site U1356 to assist correlation between the three records. A new integrated chronology offers new insights into the nature and completeness of the southern high-latitude climate histories derived from these sites

Constraining early to middle Eocene climate evolution of the southwest Pacific and Southern Ocean

Studies of early Paleogene climate suffer from the scarcity of well-dated sedimentary records from the southern Pacific Ocean, the largest ocean basin during this time. We present a new magnetostratigraphic record from marine sediments that outcrop along the mid-Waipara River, South Island, New Zealand. Fully oriented samples for paleomagnetic analyses were collected along 45 m of stratigraphic section, which encompasses magnetic polarity Chrons from C23n to C21n (~51.5-47 Ma). These results are integrated with foraminiferal, calcareous nannofossil, and dinoflagellate cyst (dinocyst) biostratigraphy from samples collected in three different expeditions along a total of ~80 m of section. Biostratigraphic data indicates relatively continuous sedimentation from the lower Waipawan to the upper Heretaungan New Zealand stages (i.e., lower Ypresian to lower Lutetian, 55.5 to 46 Ma). We provide the first magnetostratigraphically-calibrated age of 48.88 Ma for the base of the Heretaungan New Zealand stage (latest early Eocene). To improve the correlation of the climate record in this section with other Southern Ocean records, we reviewed the magnetostratigraphy of Ocean Drilling Program (ODP) Site 1172 (East Tasman Plateau) and Integrated Ocean Drilling Program (IODP) Site U1356 (Wilkes Land Margin, Antarctica). A paleomagnetic study of discrete samples could not confirm any reliable magnetic polarity reversals in the early Eocene at Site 1172. We use the robust magneto-biochronology of a succession of dinocyst bioevents that are common to mid-Waipara, Site 1172, and Site U1356 to assist correlation between the three records. A new integrated chronology offers new insights into the nature and completeness of the southern high-latitude climate histories derived from these sites